1. Field of the Invention
The present invention is related to systems for detecting target ions in a sample, and more specifically, to ion sensors comprising an ion exchanger covalently grafted to a plasticizer-free co-polymer.
2. Description of the Prior Art
Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the claims.
Highly selective chemical sensors based on molecular recognition and extraction principles are a very important, well understood class of sensors.1,2 Ion-selective electrodes (ISEs) and optodes in particular have found widespread use in clinical laboratories3 and are being explored for numerous other applications.
Traditionally, these sensors are based on hydrophobic plasticized polymeric membranes or films that are doped with one or more ionophores in addition to a lipophilic ion-exchanger. Each of these components plays an important role to the sensor response.2,4 The hydrophobicity of the polymer assures that spontaneous, non-specific electrolyte extraction from the sample is suppressed. At the same time, the membrane matrix must act as a solvent of low viscosity for all active sensing components in the film. Each ionophore acts as a lipophilic complexing agent, and the ion-exchanger is responsible to extract the analyte ions from the sample to the membrane to satisfy electroneutrality.
In many ways, the basic composition and function of these ISEs still mimics that of early liquid membrane electrodes, where all components were simply dissolved in an organic solvent. However, modern ion sensors are moving towards drastic miniaturization and these sensors are often in contact with relatively lipophilic sample environments such as undiluted whole blood. Microelectrodes have been used for a long time to probe intracellular ion compositions and are also used for chemical profiling and chemical microscopy.5 Microsphere optodes with varying compositions are today developed in view of the measurement of biological and clinical samples.6 Optical sensing spheres that are a few hundred nanometers in diameter are currently explored for intracellular ion measurements.7 These important applications expect that cross-contamination of sensors and leaching of active components from the sensor membrane are reduced or even eliminated.
Earlier work has focused on improving the lipophilicity of all sensing components for improved lifetime of these sensors. There is likely a practical limit to synthesizing ionophores and plasticizers with longer alkyl chains to make them more lipophilic,8 since they still must remain soluble in the polymeric membrane phase. One solution to the problem of insufficient retention has been the covalent attachment of all active sensing components onto the polymeric backbone. Over the years, plasticizer-free ion-selective membranes based on different materials have been evaluated. Suitable matrices include polyurethanes,9 polysiloxanes,10,11 silicone rubber,12,13 polythiophenes,14 polyacrylates,15 epoxyacrylates,16 sol-gels,17,18 methacrylic-acrylic copolymers19-22 and methacrylate copolymers.23,24 Among these, the methacrylic-acrylic copolymers and methacrylate copolymers, which are synthesized via free radical-initiated mechanisms, are attractive because various monomer combinations and the numerous polymerization methods are available to create polymers with different physical and mechanical properties. Of the plasticizer-free copolymers reported, a methyl methacrylate and decyl methacrylate copolymer (MMA-DMA) has been studied by Peper et al. (U.S. Patent Publication No. 2003/0217920) as a promising matrix, with functional ISEs23 and optodes25 reported for Li+, Na+, K+, Ca2+, and Mg2+.
Early work towards covalent attachment of ionophores made use of functionalized poly(vinyl chloride)26,27, which could not be used without plasticizer. In later work, Na+, K+ and Pb2+ selective ionophores were covalently grafted to a polysiloxane matrix and applied to the fabrication of CHEMFET sensors.10,28 Another notable direction in ionophore grafting by the sol-gel technique has been introduced by Kimura, with demonstrated applications to serum measurements.17,18. Recently, neutral ionophores were covalently attached by Pretsch and coworkers to a polyurethane membrane matrix in view of reducing ion fluxes across the membrane.29 In other recent reports, two hydrophilic crown ether-type potassium-selective ionophores, 4′-acryloylamidobenzo-15-crown-5 (AAB15C5) and 4′-acryloylamidobenzo-18-crown-6 (AAB18C6),20 a sodium-selective ionophore, 4-tertbutyl calix[4]arene tetraacetic acid tetraethyl ester,21 as well as a new calcium ionophore N,N-dicyclohexyl-N′-phenyl-N′-3-(2-propenoyl)oxyphenyl-3-oxapentanediamide (AU-1; see FIG. 1)24 have been copolymerized with other acrylate monomers by a simple one-step solution polymerization method. The simplicity of this procedure constitutes an important advantage over most other methods described above. These polymers containing grafted ionophores showed comparable selectivity and improved lifetime compared to ISEs with free, unbound ionophore present. Numerous promising approaches are therefore available to obtain plasticizer-free polymers containing covalently attached ionophores.
Unlike the grafting of ionophores, the covalent attachment of ion-exchangers has been much less explored. Reinhoudt reported on the covalent attachment of the tetraphenylborate anion, TPB−10,28 and Kimura also successfully attached a cation-exchanger (TPB−)17 as well as an anion-exchanger (tetradecyldimethyl(3-trimethoxysilylpropyl)ammonium chloride) into a sol-gel matrix.18 Unfortunately, it is known that the unsubstituted tetraphenylborate is highly susceptible to decomposition by acid hydrolysis, oxidants and light.30-32 It was also reported that ppb levels of mercury ions in aqueous solution can cause rapid decomposition of sodium tetraphenylborate and potassium tetrakis-(4-chlorophenyl) borate in plasticized PVC membranes.33 Therefore, the reported covalent attachments of a simple tetraphenylborate may likely not solve these inherent problems. Although the highly substituted derivatives, such as sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB) have a much improved stability, the borates can still be protonated under acidic conditions and subsequently hydrolyze.32 A decrease in selectivity and response slopes of ion-selective membranes after prolonged exposure to a continuous water flow was observed, which was explained on the basis of the change of ionophore and ion exchanger (NaTFPB) ratio caused by slow degradation of the borate anions.10 In addition, the preparation of highly substituted borate anions, especially asymmetric analogs, is quite difficult and synthetically complex.34,35 A further modification of these compounds, such as the preparation of polymerizable derivatives has never been reported.
It was recently shown that carboranes can be used as alternative cation-exchangers in ion selective sensors.36-38 Carboranes are a relatively new class of weakly coordination anions based on an extremely stable boron cluster framework (CB11H12−), as shown in FIG. 1. Carboranes are weakly coordinating anions that are based on a relatively stable boron cluster framework. They also have versatile functionalization chemistry, as both the boron-vertexes and carbon vertex can be chemically modified.39,40 The B—H bonds of the parent closo-dodecacarborane (CB11H12−) are somewhat hydridic and suitable for electrophilic substitution such as halogenation.
Chlorinated, brominated and iodinated carborane anions at boron atoms have been prepared by solid-state synthesis.36,37 Recently, halogenated dodecacarboranes were found to be improved cation-exchanger in terms of lipophilicity and chemical stability. These boron derivatives have a much higher lipophilicity compared to the water-soluble unsubstituted parent carborane anion, and were demonstrated to be very promising alternatives to the tetraphenylborates.36 In contrast, the C—H bond in the carborane anion is somewhat acidic. It was reported that C-lithiation of CB11H12− followed by treatment with alkyl, silyl, or phosphine halides leads to different carbon derivatives.40 Such carborane anions are quite inert chemically and electrochemically and exhibit no absorbance in the UV-Vis range. These compounds have weak coordination and ion-pair formation properties, which are attractive for ion sensing applications. Furthermore, both the boron-vertexes and carbon vertex can be quite easily modified chemically.39,40 However, the commercially available cesium carborane (CsCB11H12) is water-soluble and its poor lipophilicity limits its application as ion-exchanger. In our laboratory, therefore, a number of more lipophilic B-halogenated carborane anions were recently synthesized, and many showed nearly identical ion-exchange and improved retention properties compared to the best tetraphenylborate available, tetrakis[3,5-(trifluoromethyl)]phenyl borate (TFPB−).36,37 
In addition to potentially unparalleled lipophilicity, the carboranes possess many other characteristics that make them suitable for electrochemical applications. For example, they are not susceptible to acid and base hydrolysis and they are relatively inert to electrochemical oxidation (.about 2.0 V vs. ferrocene/ferrocenium at Pt in dichloromethane) (67). High Ih symmetry and tangentially delocalized σ-bonding make the carboranes one of the most chemically stable classes of compounds in chemistry. Furthermore, their bulky size (nearly 1 nm in diameter) and sufficient charge delocalization meet the criteria imposed for sufficient ion-exchanging. Another advantage, important for bulk optode studies, is their lack of absorption in the UV-Vis spectrum. Therefore, it is desirable to further study the carboranes for developing a more robust ion-exchanger to be used in chemical sensors.